MicroRNAs (miRNA or miR) are short (usually 18-24 nucleotides) nucleic acid molecules that are able to regulate the expression of target genes. See review by Carrington et al. Science, Vol. 301(5631):336-338, 2003). MiRNAs act as repressors of target mRNAs by promoting their degradation, when their sequences are perfectly complementary, and/or by inhibiting translation, when their sequences contain mismatches.
Without being bound by theory, mature miRNAs are believed to be generated by RNA polymerase II (pol II) or RNA polymerase III (pol III; see Qi et al. (2006) Cellular & Molecular Immunology, Vol. 3:411-419) and arise from initial transcripts termed primary miRNA transcripts (pri-miRNAs). These pri-miRNAs are frequently several thousand bases long and are therefore processed to make the much shorter mature miRNAs. This processing is believed to occur in two steps. First, pri-miRNAs are processed in the nucleus by the RNase Drosha into about 70- to about 100-nucleotide hairpin-shaped precursors (pre-miRNAs). Second, after transposition to the cytoplasm, the hairpin pre-miRNAs are further processed by the RNase Dicer to produce a double-stranded miRNA. A mature miRNA strand is then incorporated into the RNA-induced silencing complex (RISC), where it associates with its target mRNA by base-pair complementarity and leads to suppression of protein expression.
Cancer is a group of diseases characterized by uncontrolled cell division which can lead to abnormal tissue and, in turn, disruption of normal physiologic processes and, possibly, death. Cancers likely have etiologies in genetic and environmental factors. Regarding the former, cancer-critical genes can be roughly classified into two groups based on whether mutations in them cause loss of function or gain of function outcomes. Loss-of-function mutations of tumor suppressor genes relieve cells of inhibitions that normally help to hold their numbers in check, while gain-of-function mutations of proto-oncogenes stimulate cells to increase their numbers when they should not. Notable tumor suppressor genes include PTEN (phosphatase and tensin homolog), p53 (protein 53 or tumor protein 53), and INPP4B (inositol polyphosphate 4-phosphatase type II). One mechanism by which these genes can be suppressed, and thus lose their ability to suppress the onset of tumorigenesis, is through the binding of their mRNA transcripts and the inhibition of translation.
As the reduction or loss of these genes is linked to cancer development, there is a need in the art for treatment methods that can up-regulate them. Specifically, there is a need for inhibitors that target miRNAs that bind to tumor suppressor genes. Further, the art lacks in inhibitors designed to this end which can be produced cheaply, delivered effectively, and which display adequate bioavailability.